Enhlink infers distal and context-specific enhancer-promoter linkages.

Enhancers play a crucial role in regulating gene expression and their functional status can be queried with cell type precision using using single-cell (sc)ATAC-seq. To facilitate analysis of such data, we developed Enhlink, a novel computational approach that leverages single-cell signals to infer linkages between regulatory DNA sequences, such as enhancers and promoters. Enhlink uses an ensemble strategy that integrates cell-level technical covariates to control for batch effects and biological covariates to infer robust condition-specific links and their associated p-values. It can integrate simultaneous gene expression and chromatin accessibility measurements of individual cells profiled by multi-omic experiments for increased specificity. We evaluated Enhlink using simulated and real scATAC-seq data, including those paired with physical enhancer-promoter links enumerated by promoter capture Hi-C and with multi-omic scATAC-/RNA-seq data we generated from the mouse striatum. These examples demonstrated that our method outperforms popular alternative strategies. In conjunction with eQTL analysis, Enhlink revealed a putative super-enhancer regulating key cell type-specific markers of striatal neurons. Taken together, our analyses demonstrate that Enhlink is accurate, powerful, and provides features that can lead to novel biological insights.

A cross-sectional study of alcohol, opioid use, and anxiety in agriculturally based occupations.

PURPOSE: Although there are many studies that have examined substance use and mental health concerns in rural areas, there is a paucity of research related to the prevalence of substance use and mental well-being in agriculturally based occupations. This study aimed to determine the prevalence of alcohol and opioid misuse and anxiety among adults in agriculturally based occupations in the rural Midwest and to determine the risk factors for alcohol misuse. METHODS: Data were collected via mailed surveys with 1,791 surveys returned. Participants completed the Alcohol Use Disorder Identification Test, the Drug Abuse Screening Test-1, the Generalized Anxiety Disorder Screener, and reported demographic data. Multivariable logistic regression was used to examine factors associated with alcohol misuse. RESULTS: Younger age, male, not married, agriculturally based workers were significantly associated with alcohol misuse. For opioid use, the highest prevalence rate (10%) was found among direct agricultural workers who were not married and in the age group 19-39. The highest anxiety prevalence rate was found in participants aged 19-39 (15.5%) who also scored in the highest level of alcohol misuse with a prevalence rate of 27.9%. CONCLUSIONS: Future research is suggested in the areas of gender identity and anxiety in agricultural populations and agriculturally based occupations as protective factors for opioid misuse.

The collaborative cross strains and their founders vary widely in cocaine-induced behavioral sensitization.

Cocaine use and overdose deaths attributed to cocaine have increased significantly in the United States in the last 10 years. Despite the prevalence of cocaine use disorder (CUD) and the personal and societal problems it presents, there are currently no approved pharmaceutical treatments. The absence of treatment options is due, in part, to our lack of knowledge about the etiology of CUDs. There is ample evidence that genetics plays a role in increasing CUD risk but thus far, very few risk genes have been identified in human studies. Genetic studies in mice have been extremely useful for identifying genetic loci and genes, but have been limited to very few genetic backgrounds, leaving substantial phenotypic, and genetic diversity unexplored. Herein we report the measurement of cocaine-induced behavioral sensitization using a 19-day protocol that captures baseline locomotor activity, initial locomotor response to an acute exposure to cocaine and locomotor sensitization across 5 exposures to the drug. These behaviors were measured in 51 genetically diverse Collaborative Cross (CC) strains along with their inbred founder strains. The CC was generated by crossing eight genetically diverse inbred strains such that each inbred CC strain has genetic contributions from each of the founder strains. Inbred CC mice are infinitely reproducible and provide a stable, yet diverse genetic platform on which to study the genetic architecture and genetic correlations among phenotypes. We have identified significant differences in cocaine locomotor sensitivity and behavioral sensitization across the panel of CC strains and their founders. We have established relationships among cocaine sensitization behaviors and identified extreme responding strains that can be used in future studies aimed at understanding the genetic, biological, and pharmacological mechanisms that drive addiction-related behaviors. Finally, we have determined that these behaviors exhibit relatively robust heritability making them amenable to future genetic mapping studies to identify addiction risk genes and genetic pathways that can be studied as potential targets for the development of novel therapeutics.

Heritable variation in locomotion, reward sensitivity and impulsive behaviors in a genetically diverse inbred mouse panel.

Drugs of abuse, including alcohol and stimulants like cocaine, produce effects that are subject to individual variability, and genetic variation accounts for at least a portion of those differences. Notably, research in both animal models and human subjects point toward reward sensitivity and impulsivity as being trait characteristics that predict relatively greater positive subjective responses to stimulant drugs. Here we describe use of the eight collaborative cross (CC) founder strains and 38 (reversal learning) or 10 (all other tests) CC strains to examine the heritability of reward sensitivity and impulsivity traits, as well as genetic correlations between these measures and existing addiction-related phenotypes. Strains were all tested for activity in an open field and reward sensitivity (intake of chocolate BOOST®). Mice were then divided into two counterbalanced groups and underwent reversal learning (impulsive action and waiting impulsivity) or delay discounting (impulsive choice). CC and founder mice show significant heritability for impulsive action, impulsive choice, waiting impulsivity, locomotor activity, and reward sensitivity, with each impulsive phenotype determined to be non-correlating, independent traits. This research was conducted within the broader, inter-laboratory effort of the Center for Systems Neurogenetics of Addiction (CSNA) to characterize CC and DO mice for multiple, cocaine abuse related traits. These data will facilitate the discovery of genetic correlations between predictive traits, which will then guide discovery of genes and genetic variants that contribute to addictive behaviors.

Mechanisms of disease-modifying effect of saracatinib (AZD0530), a Src/Fyn tyrosine kinase inhibitor, in the rat kainate model of temporal lobe epilepsy.

We have recently demonstrated the role of the Fyn-PKCδ signaling pathway in status epilepticus (SE)-induced neuroinflammation and epileptogenesis in experimental models of temporal lobe epilepsy (TLE). In this study, we show a significant disease-modifying effect and the mechanisms of a Fyn/Src tyrosine kinase inhibitor, saracatinib (SAR, also known as AZD0530), in the rat kainate (KA) model of TLE. SAR treatment for a week, starting the first dose (25 mg/kg, oral) 4 h after the onset of SE, significantly reduced spontaneously recurring seizures and epileptiform spikes during the four months of continuous video-EEG monitoring. Immunohistochemistry of brain sections and Western blot analyses of hippocampal lysates at 8-day (8d) and 4-month post-SE revealed a significant reduction of SE-induced astrogliosis, microgliosis, neurodegeneration, phosphorylated Fyn/Src-419 and PKCδ-tyr311, in SAR-treated group when compared with the vehicle control. We also found the suppression of nitroxidative stress markers such as iNOS, 3-NT, 4-HNE, and gp91phox in the hippocampus, and nitrite and ROS levels in the serum of the SAR-treated group at 8d post-SE. The qRT-PCR (hippocampus) and ELISA (serum) revealed a significant reduction of key proinflammatory cytokines TNFα and IL-1ß mRNA in the hippocampus and their protein levels in serum, in addition to IL-6 and IL-12, in the SAR-treated group at 8d in contrast to the vehicle-treated group. These findings suggest that SAR targets some of the key biomarkers of epileptogenesis and modulates neuroinflammatory and nitroxidative pathways that mediate the development of epilepsy. Therefore, SAR can be developed as a potential disease-modifying agent to prevent the development and progression of TLE.

A Cross-sectional Study of Hospital Performance on ICU Utilization Practices for Patients with Chronic Obstructive Pulmonary Disease.

PURPOSE: Intensive care unit (ICU) resources are a costly but effective commodity used in the management of critically ill patients with chronic obstructive pulmonary disease (COPD). ICU admission decisions are determined by patient diagnosis and severity of illness, but also may be affected by hospital differences in quality and performance. We investigate the variability in ICU utilization for patients with COPD and its association with hospital characteristics. METHODS: Using a 3M administrative dataset spanning 2008-2013, we conducted a retrospective cohort study of adult patients discharged with COPD at hospitals in three state to determine variability in ICU utilization. Quality metrics were calculated for each hospital using observed-to-expected (O/E) ratios for overall mortality and length of stay. Logistic and multilevel multivariate regression models were constructed, estimating the association between hospital quality metrics on ICU utilization, after adjustment for available clinical factors and hospital characteristics. RESULTS: In 434 hospitals with 570,517 COPD patient visits, overall ICU admission rate was 33.1% [range 0-89%; median (IQR) 24% (8, 54)]. The addition of patient, hospital, and quality characteristics decreased the overall variability attributable to individual hospital differences seen within our cohort from 40.9 to 33%. Odds of ICU utilization were increased for larger hospitals and those seeing lower pulmonary case volume. Hospitals with better overall O/E ratios for length of stay or mortality had lower ICU utilization. CONCLUSIONS: Hospital characteristics, including quality metrics, are associated with variability in ICU utilization for COPD patients, with higher ICU utilization seen for lower performing hospitals.

Delayed Symptom Onset Following Pediatric Sport-Related Concussion.

Objective: (1) To examine the prevalence of delayed symptom onset (DSO) among pediatric sport-related concussion (SRC) patients as well as the effect of symptom onset on initial symptom severity, length of recovery, and development of delayed recovery; (2) to evaluate the impact of symptom onset on sideline management. Methods: We conducted a prospective study of pediatric SRC patients (<20 years of age) evaluated at a multi-disciplinary concussion program. Patients underwent initial medical assessment by a single neurosurgeon and a structured interview by a research assistant. Patients were classified as experiencing early symptom onset (symptom onset <15 min from the time of the suspected injury; ESO) or DSO (≥15 min from the time of the suspected injury). Results: A total of 144 SRC patients (61.1% male; mean age 14.6 years, SD 1.8) evaluated a median of 5.0 days (IQR 4.0, 9.0) post-injury were included in the study. Among these patients, 120 (83.3%) reported experiencing ESO while 24 (16.7%) experienced DSO following injury. Among those that experienced DSO the median length of time from the suspected injury to symptom onset was 60.0 min (IQR 20.0, 720.0). No significant differences were observed in symptom severity at initial medical assessment (median Post-Concussion Symptom Scale score 20.0 vs. 18.0, p = 0.35), length of physician-document clinical recovery (median 22.0 vs. 24.0 days; p = 0.46) or the proportion of those who developed delayed physician-documented clinical recovery (34.4 vs. 42.1%, p = 0.52) among patients with ESO or DSO. Patients who reported experiencing ESO were significantly more likely to be immediately removed from play at the time of their suspected injury compared to those who experienced DSO (71.6% vs. 29.2%; p < 0.0001). Conclusions: This study suggests that an important proportion of children and adolescents who sustain an acute SRC experience DSO. DSO is associated with lower rates of immediate removal from play at the time of suspected injury. Secondary study findings highlight the need for improved sport stakeholder concussion education and standardized concussion protocols that mandate the immediate and permanent removal of all youth with a suspected concussion until they undergo medical assessment.

Characterization of genetically complex Collaborative Cross mouse strains that model divergent locomotor activating and reinforcing properties of cocaine.

RATIONALE: Few effective treatments exist for cocaine use disorders due to gaps in knowledge about its complex etiology. Genetically defined animal models provide a useful tool for advancing our understanding of the biological and genetic underpinnings of addiction-related behavior and evaluating potential treatments. However, many attempts at developing mouse models of behavioral disorders were based on overly simplified single gene perturbations, often leading to inconsistent and misleading results in pre-clinical pharmacology studies. A genetically complex mouse model may better reflect disease-related behaviors. OBJECTIVES: Screening defined, yet genetically complex, intercrosses of the Collaborative Cross (CC) mice revealed two lines, RIX04/17 and RIX41/51, with extreme high and low behavioral responses to cocaine. We characterized these lines as well as their CC parents, CC004/TauUnc and CC041/TauUnc, to evaluate their utility as novel model systems for studying the biological and genetic mechanisms underlying behavioral responses to cocaine. METHODS: Behavioral responses to acute (initial locomotor sensitivity) and repeated (behavioral sensitization, conditioned place preference, intravenous self-administration) exposures to cocaine were assessed. We also examined the monoaminergic system (striatal tissue content and in vivo fast scan cyclic voltammetry), HPA axis reactivity, and circadian rhythms as potential mechanisms for the divergent phenotypic behaviors observed in the two strains, as these systems have a previously known role in mediating addiction-related behaviors. RESULTS: RIX04/17 and 41/51 show strikingly divergent initial locomotor sensitivity to cocaine with RIX04/17 exhibiting very high and RIX41/51 almost no response. The lines also differ in the emergence of behavioral sensitization with RIX41/51 requiring more exposures to exhibit a sensitized response. Both lines show conditioned place preference for cocaine. We determined that the cocaine sensitivity phenotype in each RIX line was largely driven by the genetic influence of one CC parental strain, CC004/TauUnc and CC041/TauUnc. CC004 demonstrates active operant cocaine self-administration and CC041 is unable to acquire under the same testing conditions, a deficit which is specific to cocaine as both strains show operant response for a natural food reward. Examination of potential mechanisms driving differential responses to cocaine show strain differences in molecular and behavioral circadian rhythms. Additionally, while there is no difference in striatal dopamine tissue content or dynamics, there are selective differences in striatal norepinephrine and serotonergic tissue content. CONCLUSIONS: These CC strains offer a complex polygenic model system to study underlying mechanisms of cocaine response. We propose that CC041/TauUnc and CC004/TauUnc will be useful for studying genetic and biological mechanisms underlying resistance or vulnerability to the stimulatory and reinforcing effects of cocaine.

Inducible nitric oxide synthase inhibitor, 1400W, mitigates DFP-induced long-term neurotoxicity in the rat model.

Chemical nerve agents (CNA) are increasingly becoming a threat to both civilians and military personnel. CNA-induced acute effects on the nervous system have been known for some time and the long-term consequences are beginning to emerge. In this study, we used diisopropylfluorophosphate (DFP), a seizurogenic CNA to investigate the long-term impact of its acute exposure on the brain and its mitigation by an inducible nitric oxide synthase (iNOS) inhibitor, 1400W as a neuroprotectant in the rat model. Several experimental studies have demonstrated that DFP-induced seizures and/or status epilepticus (SE) causes permanent brain injury, even after the countermeasure medication (atropine, oxime, and diazepam). In the present study, DFP-induced SE caused a significant increase in iNOS and 3-nitrotyrosine (3-NT) at 24 h, 48 h, 7d, and persisted for a long-term (12 weeks post-exposure), which led to the hypothesis that iNOS is a potential therapeutic target in DFP-induced brain injury. To test the hypothesis, we administered 1400W (20 mg/kg, i.m.) or the vehicle twice daily for the first three days of post-exposure. 1400W significantly reduced DFP-induced iNOS and 3-NT upregulation in the hippocampus and piriform cortex, and the serum nitrite levels at 24 h post-exposure. 1400W also prevented DFP-induced mortality in <24 h. The brain immunohistochemistry (IHC) at 7d post-exposure revealed a significant reduction in gliosis and neurodegeneration (NeuN+ FJB positive cells) in the 1400W-treated group. 1400W, in contrast to the vehicle, caused a significant reduction in the epileptiform spiking and spontaneous recurrent seizures (SRS) during 12 weeks of continuous video-EEG study. IHC of brain sections from the same animals revealed a significant reduction in reactive gliosis (both microgliosis and astrogliosis) and neurodegeneration across various brain regions in the 1400W-treated group when compared to the vehicle-treated group. A multiplex assay from hippocampal lysates at 6 weeks post-exposure showed a significant increase in several key pro-inflammatory cytokines/chemokines such as IL-1α, TNFα, IL-1ß, IL-2, IL-6, IL-12, IL-17a, MCP-1, LIX, and Eotaxin, and a growth factor, VEGF in the vehicle-treated animals. 1400W significantly suppressed IL-1α, TNFα, IL-2, IL-12, and MCP-1 levels. It also suppressed DFP-induced serum nitrite levels at 6 weeks post-exposure. In the Morris water maze, the vehicle-treated animals spent significantly less time in the target quadrant in a probe trial at 9d post-exposure compared to their time spent in the same quadrant 11 days previously (i.e., 2 days prior to DFP exposure). Such a difference was not observed in the 1400W and control groups. However, learning and short-term memory were unaffected when tested at 10-16d and 28-34d post-exposure. Accelerated rotarod, horizontal bar test, and the forced swim test revealed no significant changes between groups. Overall, the findings from this study suggest that 1400W may be considered as a potential therapeutic agent as a follow-on therapy for CNA exposure, after controlling the acute symptoms, to prevent mortality and some of the long-term neurotoxicity parameters such as epileptiform spiking, SRS, neurodegeneration, reactive gliosis in some brain regions, and certain key proinflammatory cytokines and chemokine.

Dual Modality Radiation With External Beam Radiation Therapy and Transarterial Radioembolization for Hepatocellular Carcinoma With Gross Vascular Invasion.

OBJECTIVES: Patients with hepatocellular carcinoma (HCC) and gross vascular invasion (GVI) have poor outcomes with systemic therapy such as sorafenib. Both external beam radiation therapy (EBRT) and transarterial radioembolization (TARE) have been utilized for this patient population. We sought to compare outcomes using dual modality radiation (EBRT+TARE) versus EBRT alone in patients with HCC and GVI. MATERIALS AND METHODS: Between 2011 and 2017, 45 patients with HCC and GVI were treated with EBRT±TARE at our institution. Progression-free survival (PFS) and overall survival (OS) were assessed and compared using Kaplan-Meier method and log-rank test. Univariable and multivariable Cox proportional hazards regression was used to assess the impact of the variables stage, etiology of cirrhosis, Child-Pugh (CP) score, and Karnofsky Performance Score (KPS) on PFS and OS. RESULTS: Patient characteristics were well-balanced except for KPS (80 vs. 90) and CP score. Median OS for patients receiving EBRT+TARE was 263 days (95% confidence interval [CI]: 167, -) versus 193 days (95% CI: 51, 262) for EBRT alone (P=0.049). However, this did not hold up on MVA. When EBRT and TARE were delivered within 2 months as planned (n=12), median PFS was 218 days (95% CI: 44, -) for dual modality radiation versus 63 days (95% CI: 38, 137) for EBRT alone (P=0.048). When EBRT and TARE were delivered within 6 months, the difference in PFS was no longer seen (P=NS), because some patients received TARE as a salvage therapy. CONCLUSIONS: Dual modality radiation with EBRT and TARE may be associated with improved OS in patients with HCC and GVI. Dual modality radiation may be associated with improved PFS in patients with HCC and GVI compared with EBRT alone when EBRT and TARE are delivered within 2 months of each other as part of a planned dual modality treatment strategy. However, since this is a retrospective study with inherent selection bias, these findings need further validation in a prospective clinical trial for patients with HCC and GVI.

Cervical Spine Dysfunction Following Pediatric Sports-Related Head Trauma.

OBJECTIVE: To examine the prevalence of cervical spine injuries among children and adolescents referred with suspected and diagnosed sports-related concussion (SRC); and evaluate the effect of cervical spine dysfunction (CSD) on physician-documented clinical recovery following SRC. SETTING: A multidisciplinary pediatric concussion program. PARTICIPANTS: A total of 266 patients (6-19 years) referred with suspected SRC. DESIGN: A retrospective cohort study. MAIN MEASURES: CSD defined as neurological symptoms localized to the cervical spine or the presence of neck pain, headache, or dizziness and abnormal cervical spine examination findings; physician-documented clinical recovery. RESULTS: One patient was diagnosed with a T1 compression fracture. Of the 246 patients diagnosed with SRC, 80 (32.5%) met the clinical criteria for CSD including 4 patients with central cord neuropraxia and 1 with a spinal cord injury without radiographic abnormality (SCIWORA). Excluding patients with central cord neuropraxia OR SCIWORA, patients with SRC with CSD took longer to achieve physician-documented clinical recovery (28.5 days vs 17 days, P < .0001) and were 3.95 times more likely to experience delayed physician-documented clinical recovery (>4 weeks postinjury) compared with those without CSD. CONCLUSIONS: Patients with suspected and diagnosed SRC can present with a wide spectrum of coincident cervical spine injuries. Cervical spine dysfunction may be a risk factor for delayed clinical recovery.

Do Hospitals Performing Frequent Neuraxial Anesthesia for Hip and Knee Replacements Have Better Outcomes?

BACKGROUND: Neuraxial anesthesia is increasingly recommended for hip/knee replacements as some studies show improved outcomes on the individual level. With hospital-level studies lacking, we assessed the relationship between hospital-level neuraxial anesthesia utilization and outcomes. METHODS: National data on 808,237 total knee and 371,607 hip replacements were included (Premier Healthcare 2006 to 2014; 550 hospitals). Multivariable associations were measured between hospital-level neuraxial anesthesia volume (subgrouped into quartiles) and outcomes (respiratory/cardiac complications, blood transfusion/intensive care unit need, opioid utilization, and length/cost of hospitalization). Odds ratios (or percent change) and 95% CI are reported. Volume-outcome relationships were additionally assessed by plotting hospital-level neuraxial anesthesia volume against predicted hospital-specific outcomes; trend tests were applied with trendlines' R statistics reported. RESULTS: Annual hospital-specific neuraxial anesthesia volume varied greatly: interquartile range, 3 to 78 for hips and 6 to 163 for knees. Increasing frequency of neuraxial anesthesia was not associated with reliable improvements in any of the study's clinical outcomes. However, significant reductions of up to -14.1% (95% CI, -20.9% to -6.6%) and -15.6% (95% CI, -22.8% to -7.7%) were seen for hospitalization cost in knee and hip replacements, respectively, both in the third quartile of neuraxial volume. This coincided with significant volume effects for hospitalization cost; test for trend P < 0.001 for both procedures, R 0.13 and 0.41 for hip and knee replacements, respectively. CONCLUSIONS: Increased hospital-level use of neuraxial anesthesia is associated with lower hospitalization cost for lower joint replacements. However, additional studies are needed to elucidate all drivers of differences found before considering hospital-level neuraxial anesthesia use as a potential marker of quality.

Effect of Emergency Department and ICU Occupancy on Admission Decisions and Outcomes for Critically Ill Patients.

OBJECTIVES: ICU admission delays can negatively affect patient outcomes, but emergency department volume and boarding times may also affect these decisions and associated patient outcomes. We sought to investigate the effect of emergency department and ICU capacity strain on ICU admission decisions and to examine the effect of emergency department boarding time of critically ill patients on in-hospital mortality. DESIGN: A retrospective cohort study. SETTING: Single academic tertiary care hospital. PATIENTS: Adult critically ill emergency department patients for whom a consult for medical ICU admission was requested, over a 21-month period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patient data, including severity of illness (Mortality Probability Model III on Admission), outcomes of mortality and persistent organ dysfunction, and hourly census reports for the emergency department, for all ICUs and all adult wards were compiled. A total of 854 emergency department requests for ICU admission were logged, with 455 (53.3%) as "accept" and 399 (46.7%) as "deny" cases, with median emergency department boarding times 4.2 hours (interquartile range, 2.8-6.3 hr) and 11.7 hours (3.2-20.3 hr) and similar rates of persistent organ dysfunction and/or death 41.5% and 44.6%, respectively. Those accepted were younger (mean ± SD, 61 ± 17 vs 65 ± 18 yr) and more severely ill (median Mortality Probability Model III on Admission score, 15.3% [7.0-29.5%] vs 13.4% [6.3-25.2%]) than those denied admission. In the multivariable model, a full medical ICU was the only hospital-level factor significantly associated with a lower probability of ICU acceptance (odds ratio, 0.55 [95% CI, 0.37-0.81]). Using propensity score analysis to account for imbalances in baseline characteristics between those accepted or denied for ICU admission, longer emergency department boarding time after consult was associated with higher odds of mortality and persistent organ dysfunction (odds ratio, 1.77 [1.07-2.95]/log10 hour increase). CONCLUSIONS: ICU admission decisions for critically ill emergency department patients are affected by medical ICU bed availability, though higher emergency department volume and other ICU occupancy did not play a role. Prolonged emergency department boarding times were associated with worse patient outcomes, suggesting a need for improved throughput and targeted care for patients awaiting ICU admission.

Temporal trends of transmitted HIV drug resistance in a multinational seroconversion cohort.

BACKGROUND: The rate of transmitted drug resistance (TDR) may increase with wider use of antiretroviral therapy and can contribute to therapeutic failure. We analysed time trends in TDR among HIV seroconverters. METHODS: Using CASCADE data of individuals with well estimated dates of HIV seroconversion, we examined HIV nucleotide sequences collected prior to antiretroviral therapy use from 1996-2012. All samples were taken within 12 months of testing HIV positive. Using logistic regression, we examined the association between TDR and year of seroconversion, adjusting for confounders. RESULTS: Of 4717 individuals seroconverting between 1996 and 2012, median (IQR) age at seroconversion was 33 (27, 39) years. The majority (3839; 92%) were male, mainly exposed through MSM (3767; 80%), and infected with subtype B (3464; 73%). Overall, 515 (11%) individuals had at least one drug resistance-related mutation; 280 individuals with nucleoside reverse transcriptase, 185 with nonnucleoside reverse transcriptase, and 144 with protease inhibitor mutations. Estimated TDR prevalence was 19.4% (8.2, 36.0) in 1996, significantly decreasing to 8.5% (5.9, 11.9) in 2012 [odds ratio (OR; 95% confidence interval (CI)) = 0.92 (0.90, 0.95) per year increase]. Individuals exposed through sex between men and women were significantly less likely to have been infected with a drug-resistant strain [OR (95% CI) = 0.59 (0.41, 0.87) compared with MSM], and there was marginal evidence that sampling during acute infection was associated with higher odds of resistance [OR (95% CI) = 1.20 (0.97, 1.7), P = 0.093] compared with later sampling. CONCLUSION: TDR has decreased over calendar time although a significant proportion of new infections still carry resistance-related mutations.

Application of the Eighth Edition American Joint Committee on Cancer Staging System for HPV-Related Oropharyngeal Cancer Treated With Transoral Robotic Surgery.

OBJECTIVE: Analyze patients treated with transoral robotic surgery (TORS) in the context of the eighth edition of the American Joint Committee on Cancer (AJCC) staging system. METHODS: Retrospective cohort study including 110 human papillomavirus-related oropharyngeal cancer (HPV+OPC) patients with a minimum 1-year follow-up treated with TORS between 2007 to 2016. Kaplan-Meier methods were used to estimate 3-year disease-free survival and assess differences in recurrence. RESULTS: One hundred and ten patients with a median follow-up of 54 months were analyzed. Of those, 85% of patients were male, with a median age of 60. Twenty-two percent of patients received no adjuvant therapy; 43% received adjuvant radiation; and 35% underwent adjuvant chemoradiation. Extracapsular spread was identified in 24% of patients. Overall survival was 100%, with estimated 3-year disease-free survival (DFS) (95% confidence interval) of 87% (77, 93). Under the seventh edition of the AJCC, 5% of patients were stage I; 11% were stage II; 26% were stage III; and 57% were stage IVa. Twenty-seven patients (25%) were upstaged on final pathology, whereas 15 patients (14%) were downstaged. Under the eighth edition of the AJCC, 94% of patients were stage I for both clinical and pathologic staging systems. Six patients (6%) were upstaged on final pathology, whereas six patients (6%) were downstaged. No factors demonstrated statistical significance for DFS. Within pathologic stage I, Kaplan-Meier estimates for DFS did not reach statistical significance. CONCLUSION: The majority of patients undergoing TORS for HPV + OPC are stage I under the eighth edition of the AJCC staging system, with limited pathologic re-staging compared with the prior system. Oncologic outcomes are favorable for this group. No clinicopathologic features are significant for DFS within pathologic stage I. LEVEL OF EVIDENCE: 2b. Laryngoscope, 128:1133-1139, 2018.

Association of opioid prescription and perioperative complications in obstructive sleep apnea patients undergoing total joint arthroplasties.

PURPOSE: Obstructive sleep apnea (OSA) has been linked to higher rates of perioperative complications. Practice guidelines recommend minimizing opioids in this cohort to reduce complications. However, a paucity of evidence exists relating different levels of opioid prescription to perioperative complications. Our aim was to investigate if different levels of opioid prescription are related to perioperative complication risk in patients with OSA. METHODS: A total of 107,610 OSA patients undergoing total knee or hip arthroplasty between 2006 and 2013 were identified in a nationwide database and divided into subgroups according to the amount of opioids prescribed. We then compared those subgroups for odds of perioperative complications using multilevel multivariable logistic regression models. RESULTS: OSA patients with higher levels of opioid prescription had increased odds for gastrointestinal complications (OR 1.90, 95% CI 1.47-2.46), prolonged length of stay (OR 1.64, 95% CI 1.57-1.72), and increased cost of care (OR 1.48, 95% CI 1.40-1.57). However, we found lower odds for pulmonary complications (OR 0.85, 95% CI 0.74-0.96) for the high-prescription group. CONCLUSIONS: Higher levels of opioid prescription were associated with higher odds for gastrointestinal complications and adverse effects on cost and length of stay but lower odds for pulmonary complications in OSA patients undergoing joint arthroplasties. The latter finding is unlikely causal but may represent more preventive measures and early interventions among those patients. Attempts to reduce opioid prescription should be undertaken to improve quality and safety of care in this challenging cohort in the perioperative setting.

Orientation in Virtual Reality Does Not Fully Measure Up to the Real-World.

Adult participants learned to reorient to a specific corner inside either a real or virtual rectangular room containing a distinct featural object in each corner. Participants in the virtual-reality (VR) condition experienced an immersive virtual version of the physical room using a head-mounted display (HMD) and customized manual wheelchair to provide self-movement. Following a disorientation procedure, people could reorient by using either the geometry of the room and/or the distinct features in the corners. Test trials in which the different spatial cues were manipulated revealed participants encoded features and geometry in both the real and VR rooms. However, participants in the VR room showed less facility with using geometry. Our results suggest caution must be taken when interpreting the nuances of spatial cue use in virtual environments. Reduced reliability of geometric cues in VR environments may result in greater reliance on feature cues than would normally be expected under similar real-world conditions.

Opioid prescription levels and postoperative outcomes in orthopedic surgery.

Given the basic need for opioids in the perioperative setting, we investigated associations between opioid prescription levels and postoperative outcomes using population-based data of orthopedic surgery patients. We hypothesized that increased opioid amounts would be associated with higher risk for postoperative complications. Data were extracted from the national Premier Perspective database (2006-2013); N = 1,035,578 lower joint arthroplasties and N = 220,953 spine fusions. Multilevel multivariable logistic regression models measured associations between opioid dose prescription and postoperative outcomes, studied by quartile of dispensed opioid dose. Compared to the lowest quartile of opioid dosing, high opioid prescription was associated with significantly increased odds for deep venous thrombosis and postoperative infections by approx. 50%, while odds were increased by 23% for urinary and more than 15% for gastrointestinal and respiratory complications (P < 0.001 respectively). Furthermore, higher opioid prescription was associated with a significant increase in length of stay (LOS) and cost by 12% and 6%, P < 0.001 respectively. Cerebrovascular complications risk was decreased by 25% with higher opioid dose (P = 0.004), while odds for myocardial infarction remained unaltered. In spine cases, opioid prescription was generally higher, with stronger effects observed for increase in LOS and cost as well as gastrointestinal and urinary complications. Other outcomes were less pronounced, possibly because of smaller sample size. Overall, higher opioid prescription was associated with an increase in most postoperative complications with the strongest effect observed in thromboembolic, infectious and gastrointestinal complications, cost, and LOS. Increase in complication risk occurred stepwise, suggesting a dose-response gradient.

Trends in Perioperative Practice and Resource Utilization in Patients With Obstructive Sleep Apnea Undergoing Joint Arthroplasty.

BACKGROUND: Emerging evidence associating obstructive sleep apnea (OSA) with adverse perioperative outcomes has recently heightened the level of awareness among perioperative physicians. In particular, estimates projecting the high prevalence of this condition in the surgical population highlight the necessity of the development and adherence to "best clinical practices." In this context, a number of expert panels have generated recommendations in an effort to provide guidance for perioperative decision-making. However, given the paucity of insights into the status of the implementation of recommended practices on a national level, we sought to investigate current utilization, trends, and the penetration of OSA care-related interventions in the perioperative management of patients undergoing lower joint arthroplasties. METHODS: In this population-based analysis, we identified 1,107,438 (Premier Perspective database; 2006-2013) cases of total hip and knee arthroplasties and investigated utilization and temporal trends in the perioperative use of regional anesthetic techniques, blood oxygen saturation monitoring (oximetry), supplemental oxygen administration, positive airway pressure therapy, advanced monitoring environments, and opioid prescription among patients with and without OSA. RESULTS: The utilization of regional anesthetic techniques did not differ by OSA status and overall <25% and 15% received neuraxial anesthesia and peripheral nerve blocks, respectively. Trend analysis showed a significant increase in peripheral nerve block use by >50% and a concurrent decrease in opioid prescription. Interestingly, while the absolute number of patients with OSA receiving perioperative oximetry, supplemental oxygen, and positive airway pressure therapy significantly increased over time, the proportional use significantly decreased by approximately 28%, 36%, and 14%, respectively. A shift from utilization of intensive care to telemetry and stepdown units was seen. CONCLUSIONS: On a population-based level, the implementation of OSA-targeted interventions seems to be limited with some of the current trends virtually in contrast to practice guidelines. Reasons for these findings need to be further elucidated, but observations of a dramatic increase in absolute utilization with a proportional decrease may suggest possible resource constraints as a contributor.